JP6368614B2 - Homocysteine concentration inhibitor - Google Patents
Homocysteine concentration inhibitor Download PDFInfo
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- JP6368614B2 JP6368614B2 JP2014210207A JP2014210207A JP6368614B2 JP 6368614 B2 JP6368614 B2 JP 6368614B2 JP 2014210207 A JP2014210207 A JP 2014210207A JP 2014210207 A JP2014210207 A JP 2014210207A JP 6368614 B2 JP6368614 B2 JP 6368614B2
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- cell wall
- homocysteine concentration
- chlorella pyrenoidosa
- chlorella
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Description
本発明は、MTHFR遺伝子型が変異ホモ型である場合の血漿総ホモシステイン濃度を低下させ又は上昇を防ぐためのホモシステイン濃度抑制剤に関する。 The present invention relates to a homocysteine concentration inhibitor for decreasing or preventing an increase in plasma total homocysteine concentration when the MTHFR genotype is a mutant homotype.
血漿総ホモシステイン濃度が高いと、心血管疾患やアルツハイマー病等の発病リクスが高まる。特に、MTHFR遺伝子型が変異ホモ型である場合、血漿総ホモシステイン濃度が高値となり易いため、心血管疾患やアルツハイマー病等の発病率が高い。 When the plasma total homocysteine concentration is high, pathogenic risk such as cardiovascular disease and Alzheimer's disease increases. In particular, when the MTHFR genotype is a mutant homotype, the plasma total homocysteine concentration tends to be high, and the incidence of cardiovascular disease, Alzheimer's disease, etc. is high.
この点において、MTHFR遺伝子型が変異ホモ型である場合に血漿総ホモシステイン濃度を低下させ又は上昇を防ぐ手段に対する要望は強い。 In this regard, there is a strong demand for a means for reducing or preventing an increase in plasma total homocysteine concentration when the MTHFR genotype is a mutant homotype.
特開２００９−１７３６４０号公報には、ビタミンＢ６、Ｂ１２、葉酸からなるビタミン群のうちの１種又は２種以上の成分と、セサミン類とを含有し、ビタミンＢ群の総重量が、セサミン類の総重量を１００として、１〜５００（重量比）である、血中ホモシステイン濃度を低下させ、あるいは上昇を抑制しうる組成物が開示されている。 Japanese Patent Application Laid-Open No. 2009-173640 contains one or more components in the vitamin group consisting of vitamins B6, B12 and folic acid and sesamins, and the total weight of the vitamin B group is sesamin The composition which can reduce the homocysteine density | concentration in blood which is 1-500 (weight ratio) by making the total weight of 100 into 100, or can suppress a raise is disclosed.
この組成物は、高ホモシステイン血症及びそれに関連する疾患の予防、改善及び治療に有効であるとされている。 This composition is said to be effective in the prevention, amelioration and treatment of hyperhomocysteinemia and related diseases.
しかしながら、特開２００９−１７３６４０号公報には、MTHFR遺伝子型が変異ホモ型である場合の血漿総ホモシステイン濃度の低下について記述は見当たらない。 However, Japanese Patent Application Laid-Open No. 2009-173640 does not describe a decrease in plasma total homocysteine concentration when the MTHFR genotype is a mutant homotype.
本発明は、上記のような点に鑑み行われたものであって、その目的とするところは、長期に亙って安全且つ簡便に投与し得る、MTHFR遺伝子型が変異ホモ型である場合の血漿総ホモシステイン濃度を低下させ又は上昇を防ぐためのホモシステイン濃度抑制剤を提供することにある。 The present invention has been made in view of the above points, and its object is to provide safe and simple administration over a long period of time when the MTHFR genotype is a mutant homotype. An object of the present invention is to provide a homocysteine concentration inhibitor for reducing or preventing an increase in plasma total homocysteine concentration.
本発明のホモシステイン濃度抑制剤は、次のように表すことができる。 The homocysteine concentration inhibitor of the present invention can be expressed as follows.
(1) MTHFR遺伝子型が変異ホモ型である場合の血漿総ホモシステイン濃度を低下させ又は上昇を防ぐための、クロレラ・ピレノイドサの細胞壁破砕物からなるホモシステイン濃度抑制剤。 (1) A homocysteine concentration inhibitor comprising a cell wall disruption product of chlorella pyrenoidosa for reducing or preventing an increase in plasma total homocysteine concentration when the MTHFR genotype is a mutant homotype.
(2) 経口投与剤である上記(1)記載のホモシステイン濃度抑制剤。 (2) The homocysteine concentration inhibitor according to the above (1), which is an orally administered agent.
(3) MTHFR遺伝子型が変異ホモ型である場合に推奨される葉酸服用量の４２重量％の葉酸を含有する量の経口投与により血漿総ホモシステイン濃度を低下させ又は上昇を防ぎ得る上記(2)記載のホモシステイン濃度抑制剤。 (3) When the MTHFR genotype is a mutant homotype, the plasma total homocysteine concentration can be reduced or prevented from rising by oral administration of an amount containing folic acid at 42% by weight of the recommended folic acid dose (2 ) Homocysteine concentration inhibitor.
(4) 上記クロレラ・ピレノイドサの細胞壁破砕物が、容量の８０乃至８５％の多数の直径０．５乃至１．５mmのグラスビーズが封入された密閉シリンダー内で、そのグラスビーズをクロレラ・ピレノイドサ濃度１０乃至２５重量％のクロレラ・ピレノイドサ粉体・水懸濁液と混和・回転することにより、その懸濁液中のクロレラ・ピレノイドサを摩砕することによって得られたものである上記(1)乃至(3)の何れか１項に記載のホモシステイン濃度抑制剤。 (4) The chlorella pyrenoidosa cell wall crushed material is contained in a sealed cylinder in which a large number of glass beads having a diameter of 0.5 to 1.5 mm, which is 80 to 85% of the volume, is enclosed. (1) to (1) to (10) above, which are obtained by mixing and rotating with 10 to 25% by weight of chlorella / pyrenoid powder / water suspension to grind chlorella / pirenoid powder in the suspension. The homocysteine concentration inhibitor according to any one of (3).
(5) 上記クロレラ・ピレノイドサの細胞壁破砕物が、クロレラ・ピレノイドサの細胞壁が９５％以上破砕されたものである上記(1)乃至(4)の何れか１項に記載のホモシステイン濃度抑制剤。 (5) The homocysteine concentration inhibitor according to any one of (1) to (4) above, wherein the cell wall disrupted product of Chlorella pyrenoidosa is obtained by crushing 95% or more of the cell wall of Chlorella pyrenoidosa.
(6) 上記クロレラ・ピレノイドサの細胞壁破砕物が、細胞壁破砕クロレラ・ピレノイドサの乾燥粉末である上記(1)乃至(5)の何れか１項に記載のホモシステイン濃度抑制剤。 (6) The homocysteine concentration inhibitor according to any one of (1) to (5) above, wherein the cell wall disrupted product of chlorella pyrenoidosa is a dry powder of cell wall disrupted chlorella pyrenoidosa.
本発明のホモシステイン濃度抑制剤は、長期に亙って安全且つ簡便に投与し得、MTHFR遺伝子型が変異ホモ型である場合の血漿総ホモシステイン濃度を効果的に低下させ又は上昇を効果的に防ぎ得る。 The homocysteine concentration inhibitor of the present invention can be safely and easily administered over a long period of time, effectively reducing or increasing the plasma total homocysteine concentration when the MTHFR genotype is a mutant homotype. Can prevent.
本発明におけるクロレラ・ピレノイドサとは、クロレラ属（Chlorella) に属する単細胞緑藻類のうちのChlorella pyrenoidosa種を言う。 Chlorella pyrenoidosa in the present invention refers to Chlorella pyrenoidosa species among unicellular green algae belonging to the genus Chlorella.
本発明のホモシステイン濃度抑制剤におけるクロレラ・ピレノイドサの細胞壁破砕物は、例えば、容量の８０乃至８５％の多数の直径０．５乃至１．５mmのグラスビーズが封入された密閉シリンダー内で、そのグラスビーズをクロレラ・ピレノイドサ濃度１０乃至２５重量％のクロレラ・ピレノイドサ粉体・水懸濁液と混和・回転することにより、その懸濁液中のクロレラ・ピレノイドサを摩砕することによって得ることができる。 The cell wall crushed material of chlorella pyrenoidosa in the homocysteine concentration inhibitor of the present invention is, for example, in a closed cylinder in which a large number of glass beads having a diameter of 0.5 to 1.5 mm, which is 80 to 85% of the capacity, is enclosed. By mixing and rotating glass beads with chlorella pyrenoids powder / water suspension having a chlorella pyrenoids concentration of 10 to 25% by weight, it can be obtained by grinding the chlorella pyrenoids in the suspension. .
より具体的には、例えば、先ずクロレラ・ピレノイドサ濃度１０乃至２５重量％のクロレラ・ピレノイドサ粉体・水懸濁液を１０℃以下に調整する。次にこの懸濁液を、下記のような湿式微粉砕機に送入し、破砕直後のスラリーが４０℃以下になるよう微粉砕する。次いで、このようにして得られたクロレラ・ピレノイドサのスラリーを、直ちに１０℃以下に冷却することにより、細胞壁が破砕されたクロレラ・ピレノイドサを、品質劣化を生じさせることなく得ることができる。 More specifically, for example, first, a chlorella pyrenoidosa powder / water suspension having a chlorella pyrenoidosa concentration of 10 to 25% by weight is adjusted to 10 ° C. or lower. Next, this suspension is fed into a wet pulverizer as described below, and pulverized so that the slurry immediately after crushing is 40 ° C. or lower. Next, the slurry of chlorella pyrenoids obtained in this manner is immediately cooled to 10 ° C. or lower, so that the chlorella pyrenoids having the cell walls crushed can be obtained without causing quality deterioration.
上記湿式微粉砕機は、冷却外套を持つ密閉シリンダー中に多数の直径０．５乃至１．５mmのグラスビーズが封入されたものである。そのグラスビーズ容量は密閉シリンダー容量の８０乃至８５％であり、グラスビーズを懸濁液と混和・回転することにより、懸濁液中の物質を摩砕するものである。この湿式微粉砕機は、流入する懸濁液を連続的に処理する連続湿式微粉砕機であることが好ましい。 In the wet pulverizer, a large number of glass beads having a diameter of 0.5 to 1.5 mm are enclosed in a closed cylinder having a cooling mantle. The glass bead capacity is 80 to 85% of the closed cylinder capacity, and the glass beads are mixed and rotated with the suspension to grind the substance in the suspension. The wet pulverizer is preferably a continuous wet pulverizer that continuously processes the inflowing suspension.
このような破砕方法により、クロレラ・ピレノイドサの細胞壁が９５％以上破砕されたクロレラ・ピレノイドサの細胞壁破砕物を得ることも可能である。クロレラ・ピレノイドサの細胞壁が９５％以上破砕されていること、すなわち細胞壁が破砕されているクロレラ・ピレノイドサ細胞の比率が９５％以上であることは、例えば、血球計算盤を用いて確認することができる。本発明において用いるクロレラ・ピレノイドサの細胞壁破砕物は、クロレラ・ピレノイドサの細胞壁が９５％以上破砕されたものであることが望ましい。 By such a crushing method, it is also possible to obtain a chlorella pyrenoidosa cell wall crushed material in which 95% or more of the cell wall of chlorella pyrenoidosa has been crushed. It can be confirmed, for example, using a hemocytometer that the cell wall of Chlorella pyrenoidosa is crushed by 95% or more, that is, the ratio of Chlorella pyrenoidosa cells whose cell wall is crushed is 95% or more. . The cell wall crushed material of Chlorella pyrenoidosa used in the present invention is preferably one in which the cell wall of Chlorella pyrenoidosa is crushed by 95% or more.
このようにして細胞壁が破砕されたクロレラ・ピレノイドサは、真空乾燥後粉砕を行う等の適宜の処理を施した後に使用することが好ましい。 It is preferable to use the chlorella pyrenoids with the cell wall crushed in this way after being subjected to an appropriate treatment such as pulverization after vacuum drying.
本発明のホモシステイン濃度抑制剤は、MTHFR遺伝子型が変異ホモ型である場合の血漿総ホモシステイン濃度を低下させ又は上昇を防ぐためのものであって、クロレラ・ピレノイドサの細胞壁破砕物からなる。 The homocysteine concentration-inhibiting agent of the present invention is for reducing or preventing an increase in the plasma total homocysteine concentration when the MTHFR genotype is a mutant homotype, and consists of a cell wall disruption of Chlorella pyrenoidosa.
MTHFR遺伝子型が変異ホモ型である場合、血漿総ホモシステイン濃度が高値となり易いため、心血管疾患やアルツハイマー病等の発病率が高いが、クロレラ・ピレノイドサの細胞壁破砕物からなる本発明のホモシステイン濃度抑制剤を投与することにより、血漿総ホモシステイン濃度を低下させ又は上昇を防いで、MTHFR遺伝子型が変異ホモ型である場合の前記発病率を効果的に低下させることができる。 When the MTHFR genotype is a mutant homotype, the plasma total homocysteine concentration tends to be high, so the incidence of cardiovascular disease and Alzheimer's disease is high, but the homocysteine of the present invention comprising a cell wall disruption of chlorella pyrenoidosa By administering a concentration inhibitor, the plasma total homocysteine concentration can be reduced or prevented from rising, and the disease incidence when the MTHFR genotype is a mutant homotype can be effectively reduced.
クロレラ・ピレノイドサの細胞壁破砕物からなる本発明のホモシステイン濃度抑制剤は、経口投与に適し、MTHFR遺伝子型が変異ホモ型である成人に対する投与量は、例えば、クロレラ・ピレノイドサの細胞壁破砕物の乾燥重量において１日当り６乃至２０ｇ程度（葉酸含有量が１６８乃至４２０μgである量）が適当であり、例えば８乃至１２ｇであるが、これらに限定されるものではない。クロレラ・ピレノイドサの細胞壁破砕物は人体に対する毒性を有しない。 The inhibitor of homocysteine concentration of the present invention comprising a cell wall disruption of chlorella pyrenoidosa is suitable for oral administration, and the dosage for an adult having a mutant homotype of MTHFR genotype is, for example, drying of cell wall disruption of Chlorella pyrenoidosa A weight of about 6 to 20 g per day (a quantity with a folic acid content of 168 to 420 μg) is appropriate, for example, 8 to 12 g, but is not limited thereto. The cell wall fragment of Chlorella pyrenoidosa has no toxicity to the human body.
本発明のホモシステイン濃度抑制剤は、MTHFR遺伝子型が変異ホモ型である場合に推奨される葉酸服用量の４２重量％の葉酸を含有する量の経口投与により血漿総ホモシステイン濃度を効果的に低下させ又は上昇を効果的に防ぐことができる。MTHFR遺伝子型が変異ホモ型の場合、血漿総ホモシステイン濃度が高く、葉酸の吸収効率が低いため、成人で１日当り４００μgの葉酸の摂取が推奨されている。ところが、本発明のホモシステイン濃度抑制剤の場合、クロレラ・ピレノイドサの細胞壁破砕物の乾燥重量において１日当り８ｇ（葉酸含有量が１６８μgである量）のホモシステイン濃度抑制剤を例えば３ヶ月程度の相当期間にわたり経口投与することにより、MTHFR遺伝子型が変異ホモ型の場合の血漿総ホモシステイン濃度を効果的に低下させ又は上昇を効果的に防ぐことができ、更なる期間にわたる経口投与によってその効果が持続する。 The homocysteine concentration inhibitor of the present invention effectively reduces the total plasma homocysteine concentration by oral administration of an amount containing 42% by weight of folic acid as the recommended folic acid dose when the MTHFR genotype is a mutant homotype. Lowering or raising can be effectively prevented. When the MTHFR genotype is a mutant homotype, the intake of 400 μg folic acid per day is recommended for adults because the plasma total homocysteine concentration is high and the absorption efficiency of folic acid is low. However, in the case of the homocysteine concentration inhibitor of the present invention, 8 g of the homocysteine concentration inhibitor per day (the amount in which the folic acid content is 168 μg) in the dry weight of the cell wall crushed material of Chlorella pyrenoidosa is equivalent to, for example, about 3 months. By oral administration over a period, the plasma total homocysteine concentration can be effectively reduced or prevented when the MTHFR genotype is a mutant homozygote. continue.
なお、本発明のホモシステイン濃度抑制剤は、MTHFR遺伝子型が変異ホモ型である場合に推奨される葉酸服用量の４２重量％を超える葉酸を含有する量の経口投与によっても血漿総ホモシステイン濃度を低下させ又は上昇を防ぐことができる。また、MTHFR遺伝子型が変異ホモ型である場合に推奨される葉酸服用量の４２重量％未満の葉酸を含有する量の本発明のホモシステイン濃度抑制剤の経口投与によっても血漿総ホモシステイン濃度が低下し又は上昇が防がれることは可能である。 The homocysteine concentration-inhibiting agent of the present invention can be obtained by oral administration of an amount containing folic acid exceeding 42% by weight of the recommended folic acid dose when the MTHFR genotype is a mutant homotype. Can be reduced or prevented from rising. The plasma total homocysteine concentration can also be increased by oral administration of the homocysteine concentration inhibitor of the present invention in an amount containing folic acid of less than 42% by weight of the recommended folic acid dose when the MTHFR genotype is a mutant homotype. It is possible to prevent a decrease or an increase.
本発明のホモシステイン濃度抑制剤における経口投与の形態に特に限定はないが、例えば、粉末、錠剤、硬カプセル剤、軟カプセル剤とすることができる。 The form of oral administration in the homocysteine concentration inhibitor of the present invention is not particularly limited, and for example, it can be a powder, a tablet, a hard capsule, or a soft capsule.
また種々の形態を形成する上で、各種賦形剤、結合剤、崩壊剤、滑沢剤、コーティング剤、着色剤、矯味剤、矯臭剤、可塑剤等を適宜用いることができる。 In forming various forms, various excipients, binders, disintegrants, lubricants, coating agents, coloring agents, flavoring agents, flavoring agents, plasticizers, and the like can be appropriately used.
賦形剤の例としては、糖類（乳糖，白糖，ブドウ糖，マンニトール），デンプン（バレイショ，コムギ，トウモロコシ），無機物（炭酸カルシウム，硫酸カルシウム，炭酸水素ナトリウム，塩化ナトリウム），結晶セルロース，植物末（カンゾウ末，ゲンチアナ末）、レシチン等を挙げることができる。 Examples of excipients include sugars (lactose, sucrose, glucose, mannitol), starch (potato, wheat, corn), minerals (calcium carbonate, calcium sulfate, sodium bicarbonate, sodium chloride), crystalline cellulose, plant powder ( Licorice powder, gentian powder), lecithin and the like.
結合剤の例としては、デンプンのり液，アラビアゴム，ゼラチン，アルギン酸ナトリウム，メチルセルロース（ＭＣ），エチルセルロース（ＥＣ），ポリビニルピロリドン（ＰＶＰ），ポリビニルアルコール（ＰＶＡ），ヒドロキシプロピルセルロース（ＨＰＣ），カルポキシメチルセルロース（ＣＭＣ）等を挙げることができる。 Examples of binders include starch paste, gum arabic, gelatin, sodium alginate, methyl cellulose (MC), ethyl cellulose (EC), polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), carboxy. Examples thereof include methyl cellulose (CMC).
崩壊剤の例としては、デンプン，寒天，ゼラチン末，結晶セルロース，ＣＭＣ・Ｎａ，ＣＭＣ・Ｃａ，炭酸カルシウム，炭酸水素ナトリウム，アルギン酸ナトリウム等を挙げることができる。 Examples of the disintegrant include starch, agar, gelatin powder, crystalline cellulose, CMC / Na, CMC / Ca, calcium carbonate, sodium hydrogen carbonate, sodium alginate and the like.
滑沢剤の例としては、ステアリン酸マグネシウム，タルク，水素添加植物油，マクロゴール，シリコーン油等を挙げることができる。 Examples of lubricants include magnesium stearate, talc, hydrogenated vegetable oil, macrogol, silicone oil and the like.
コーティング剤の例としては、糖衣（白糖，ＨＰＣ，セラック），膠衣（ゼラチン，グリセリン，ソルビトール），フイルムコーティング〔ヒドロキシプロピルメチルセルロース（ＨＰＭＣ），ＥＣ，ＨＰＣ，ＰＶＰ〕，腸溶性コーティング〔ヒドロキシプロビルメチルセルロースフタレート（ＨＰＭＣＰ），セルロースアセテートフタレート（ＣＡＰ）〕等を挙げることができる。 Examples of coating agents include sugar coating (sucrose, HPC, shellac), glue (gelatin, glycerin, sorbitol), film coating [hydroxypropyl methylcellulose (HPMC), EC, HPC, PVP], enteric coating [hydroxyprovir Methyl cellulose phthalate (HPMCP), cellulose acetate phthalate (CAP)] and the like.
着色剤の例としては、水溶性食用色素，レーキ色素）等を挙げることができる。矯味剤の例としては、乳糖，白糖，ブドウ糖，マンニトール）等を挙げることができる。矯臭剤の例としては、芳香性精油類），光線遮断剤（酸化チタン）等を挙げることができる。可塑剤の例としては、フタル酸エステル類，植物油，ポリエチレングリコール）等を挙げることができる。 Examples of the colorant include water-soluble food dyes and lake dyes. Examples of the corrigent include lactose, sucrose, glucose, mannitol) and the like. Examples of flavoring agents include aromatic essential oils) and light blocking agents (titanium oxide). Examples of the plasticizer include phthalic acid esters, vegetable oils, polyethylene glycol) and the like.
クロレラ・ピレノイドサの細胞壁破砕物の経口投与が血漿総ホモシステイン濃度に与える効果についての試験を行った。 The effect of oral administration of chlorella pyrenoidosa cell wall disruption on plasma total homocysteine concentration was examined.
１．被験物質の製造 1. Manufacture of test substances
被験物質である細胞壁を破砕したクロレラ・ピレノイドサ（Chlorella pyrenoidosa）の乾燥粉末（以下、単に「クロレラ」とも言う。）を、次のように製造した。 A dry powder of Chlorella pyrenoidosa (hereinafter, also simply referred to as “chlorella”) in which the cell wall as a test substance was crushed was produced as follows.
冷却外套を持つ密閉シリンダー中にその密閉シリンダー容量の８０乃至８５％の容量の多数の直径０．５乃至１．５mmのグラスビーズが封入されており、そのグラスビーズを流入液体と混和・回転することにより流入液体中の物質を摩砕する連続湿式微粉砕機（商品名：ダイノーミル［KD型］ WAB, Inc.製）に、１０℃以下に調整されたクロレラ・ピレノイドサ濃度１０乃至２５重量％のクロレラ・ピレノイドサ粉体・水懸濁液を送入して、破砕直後のスラリーが４０℃以下になるよう微粉砕し、次いで、このようにして得られたクロレラ・ピレノイドサスラリーを、直ちに１０℃以下に冷却し、真空乾燥後、粉砕することにより、被験物質である細胞壁破砕クロレラ・ピレノイドサの乾燥粉末が得られた。この細胞壁破砕クロレラ・ピレノイドサは、クロレラ・ピレノイドサの細胞壁が９５％以上破砕されたものである。 A large number of glass beads of 0.5 to 1.5 mm in diameter with a capacity of 80 to 85% of the capacity of the sealed cylinder are enclosed in a sealed cylinder having a cooling jacket, and the glass beads are mixed and rotated with the inflowing liquid. In a continuous wet pulverizer (trade name: DYNOMILL [KD type, manufactured by WAB, Inc.) that crushes substances in the inflowing liquid, the concentration of chlorella pyrenoids adjusted to 10 ° C. or lower is 10 to 25% by weight. The chlorella / pyrenoid powder / water suspension was fed and pulverized so that the slurry immediately after crushing was 40 ° C. or lower, and then the chlorella / pyrenoid slurry thus obtained was immediately cooled to 10 ° C. By cooling to the following, pulverizing after vacuum drying, a dry powder of cell wall-crushed chlorella pyrenoidosa as a test substance was obtained. This cell wall disrupted chlorella pyrenoidosa is obtained by crushing 95% or more of the cell wall of chlorella pyrenoidosa.
２．被験者 2. subject
疾病の治療中ではない３０歳以上５５歳以下の成人男性であって、MTHFR遺伝子型が、野生型である者、変異ヘテロ型である者、及び、変異ホモ型である者を被験者とした。
The subjects were
但し、下記何れかに該当するものは除外した。
1) 臨床評価に影響を与える薬物治療（漢方や民間療法を含む）をしている者（肥満症などの治療）
2) 肝、腎、心、肺、消化器、血液、内分泌系及び代謝系等に重篤な疾患・既往歴のある者
3) 生活習慣および食習慣が極度に乱れている者、あるいは不定期に激しい運動をしている者
4) アルコール多飲者
5) 食物及び薬物等にアレルギーのある者
6) 肥満を伴わない糖尿病、高血圧症、脂質異常症などで、遺伝要因等の他の影響が大きく関与していると考えられる者
7) ワーファリンを服用している者
8) 他の試験に参加している者
However, those that fall under any of the following were excluded.
1) Those who are taking medications (including Kampo and folk remedies) that affect clinical evaluation (treatment of obesity, etc.)
2) Persons with severe illness or history of liver, kidney, heart, lung, digestive organs, blood, endocrine system, metabolic system, etc.
3) Those whose lifestyle and eating habits are extremely disturbed, or those who are strenuously exercising irregularly
4) Alcoholic drinkers
5) Those who are allergic to food and drugs
6) Diabetes without obesity, hypertension, dyslipidemia, etc., and other influences such as genetic factors are considered to be greatly involved
7) Person taking warfarin
8) Participants in other trials
３．試験方法 3. Test method
１２ヶ月間にわたり、被験物質である細胞壁破砕クロレラ・ピレノイドサの乾燥粉末を１日当たり８ｇ経口投与し５回の採血検査を行う試験をオープン試験で行った。なお、試験開始前４週間は被験物質の投与は行わなかった。 Over a period of 12 months, an open test was conducted in which 8 g of a dry powder of cell wall-disrupted Chlorella pyrenoidosa, which is a test substance, was orally administered per day and five blood sampling tests were performed. The test substance was not administered for 4 weeks before the start of the test.
採血は、ベースライン、並びに、試験開始から３ヶ月後、６ヶ月後、９ヶ月後、及び１２ヶ月後に、それぞれ行い、生化学検査を行うと共に、マイクロアレイで遺伝子の発現変動を解析した。 Blood collection was performed at baseline, 3 months, 6 months, 9 months, and 12 months after the start of the test, biochemical examinations were performed, and gene expression changes were analyzed with a microarray.
４．結果 4). result
採血検査に基づく血漿総ホモシステイン濃度、血清葉酸濃度、血清ビタミンＢ１２濃度、及び血清ビタミンＤ濃度の測定結果を、表１乃至４、及び、図１乃至４に示す。 Tables 1 to 4 and FIGS. 1 to 4 show the measurement results of plasma total homocysteine concentration, serum folate concentration, serum vitamin B12 concentration, and serum vitamin D concentration based on the blood sampling test.
試験開始前の被験者の葉酸、ビタミンＢ１２、及びビタミンＤの摂取量は食事摂取基準を上回っていた。 Subjects' intake of folic acid, vitamin B12, and vitamin D before the start of the test exceeded the dietary intake standard.
しかしながら、ベースラインにおいて、MTHFR遺伝子型が変異ホモ型である者の血漿総ホモシステイン濃度は、MTHFR遺伝子型が野生型である者及び変異ヘテロ型である者の血漿総ホモシステイン濃度よりもかなり高く、基準上限値を大幅に上回っていた。また、ベースラインにおいて、MTHFR遺伝子型が変異ホモ型である者の血清葉酸濃度、血清ビタミンＢ１２濃度、及び血清ビタミンＤ濃度は、MTHFR遺伝子型が野生型である者及び変異ヘテロ型である者のそれらよりも低かった。 However, at baseline, the plasma total homocysteine concentration of those with a mutant homozygous MTHFR genotype is significantly higher than the plasma homocysteine concentration of those with a wild-type MTHFR genotype and those with a mutant heterotype. , Was significantly above the standard upper limit. In addition, the serum folate concentration, serum vitamin B12 concentration, and serum vitamin D concentration of persons with MTHFR genotypes that are mutant homotypes at baseline are those of those with MTHFR genotypes of wild type and those of mutant heterotypes. It was lower than them.
試験開始より３ヶ月後以降は、MTHFR遺伝子型が変異ホモ型である者のみ、血漿総ホモシステイン濃度がベースラインよりも大きく低下した値となった。 After 3 months from the start of the test, the plasma total homocysteine concentration was significantly lower than the baseline only for those with a mutant homozygous MTHFR genotype.
また、MTHFR遺伝子型が何れであるかにかかわらず、試験開始より３ヶ月後には血清葉酸濃度、血清ビタミンＢ１２濃度、及び血清ビタミンＤ濃度が上昇した。 Regardless of the MTHFR genotype, serum folate concentration, serum vitamin B12 concentration, and serum vitamin D concentration increased 3 months after the start of the test.
また、試験開始時と試験終了時で発現変動量に有意差を示すビタミン代謝関連の20遺伝子(p <= .05)が抽出でき、中でも葉酸輸送を担うSLC46A1遺伝子の発現亢進(p = .02, 1.4倍)が確認された。 In addition, 20 genes related to vitamin metabolism (p <= .05) showing a significant difference in the expression fluctuation amount at the start and end of the study can be extracted, and in particular, the expression of the SLC46A1 gene responsible for folate transport is increased (p = .02). , 1.4 times).
更に、試験の開始から終了にわたり、MTHFR遺伝子型が変異ホモ型である者でMTHFR遺伝子発現が緩やかに上昇した。 Furthermore, from the start to the end of the test, MTHFR gene expression gradually increased in those with a mutant homozygous MTHFR genotype.
以上のように、被験物質の３ヶ月以上の経口投与により、MTHFR遺伝子型が変異ホモ型である場合のみ、血漿総ホモシステイン濃度が大きく低下し、また、MTHFR遺伝子型が野生型であるか、変異ヘテロ型であるか、変異ホモ型であるかにかかわらず、血清葉酸濃度、血清ビタミンＢ１２濃度、及び血清ビタミンＤ濃度が上昇した。 As described above, when the test substance is orally administered for 3 months or more, only when the MTHFR genotype is a mutant homotype, the plasma total homocysteine concentration is greatly reduced, and whether the MTHFR genotype is a wild type, Serum folate concentration, serum vitamin B12 concentration, and serum vitamin D concentration increased regardless of whether it was a mutant heterotype or a mutant homotype.
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